Gene expression is regulated by complex interactions between proteins such as transcription factors and genetic material. Factors that influence the process include DNA methylation, ATP-dependent chromatin remodeling, and modification of histones by dynamic acetylation and deacetylation of ε-amino groups on certain lysine residues (Wang et al., Mol. Cell. Biol., 19:7816-7827, 1999). The enzymes responsible for reversible acetylation and deacetylation processes are histone acetyltransferases (HATs) and histone deacetylases (HDACs or HDAcs), respectively (Grozinger et al, Proc. Natl. Acad. Sci. USA, 96:4868-4873, 1999).
Mammalian HDAcs have been categorized based on sequence similarity (see, for example, Khochbin et al., Curr. Opin. Genet Dev. 11:162-166, 2001) and it is the Class III HlDAcs that include the yeast Sir2-like proteins and other sirtuins. Sirtuins are NAD-dependent deacetylases, which distinguishes them from other HDAcs. The yeast Sir2 protein was among the first sirtuins studied, and it was determined to play a role in mating switch silencing. Later, in yeast, fly and worm models, Sir2 was shown to influence the aging process and promote longevity.
Humans have seven distinct sirtuin gene products, which are localized in the nucleus, cytoplasm, and mitochondria, and are thought to play important and diverse regulatory roles in specialized mammalian cells. The mammalian correlate of the yeast Sir2 protein is SIRT1. Activation of SIRT1 with the small molecule resveratrol prolonged the lifespan of flies and wors. Human sirtuin 2 (SIRT2) is localized to the cytoplasm and has been implicated in the process of cell division via deacetylation of α-tubulin, a well-known SIRT2 substrate. Other substrates may include the transcription factor p53 and histone H3/H4. Human sirtuin 3 (SIRT3) and human sirtuin 4 (SIRT4) are mitochondrial proteins that are not yet well understood. The substrates for these enzymes have yet to be identified. Even less is currently known about SIRT5 and SIRT6.